The functions of serotonin in mammals are numerous and include control of appetite, sleep, memory and learning, temperature regulation, mood (e.g., depression), behavior (including sexual and hallucinogenic behavior), cardiovascular function, muscle contraction, and endocrine regulation. Small molecules that manipulate serotonin neurotransmission include drugs of major importance and provide a sizable percentage of the revenue of the pharmaceutical industry. These drugs include the first generation tricyclic antidepressants, such as amytryptyline, imipramine, and chlomipramine; serotonin selective reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, and paroxetine; monoamine oxidase inhibitors; other antidepressants, such as citalopram; migraine medications, such as sumatriptan and rizatriptan; and anti-emetics, such as granisetron and ondansetron. The site of action of the reuptake inhibitors and many of the other drugs listed above is purported to be the serotonin reuptake transporter (SERT). SERTs have been cloned from numerous species, including Drosophila melanogaster, mice, and humans. The cloning of SERTs from numerous species has facilitated extensive structure-function and pharmacological studies, where the conservation of amino acid residues during evolution has provided key insights into the regions of the transporter that are relevant for serotonin binding and transport, as well as for the binding of the various drugs that affect the function of the transporter.
Drugs acting at SERTs, however, have many side effects, and very little is known about the mechanism(s) causing these side effects. Drug side effects are detrimental in several ways. They prevent drugs from being used at doses that might be more effective at treating the primary indication, and sometimes the side effects may be so prohibitively noxious that a particular compound never reaches the market, or can only be used with a subset of the patient population for which it might otherwise be effective. An understanding of the causes of these side effects and determination of the genes and pathways that are affected would allow the use of rational drug design and/or combination drug therapy, leading to more efficient, safe, and better tolerated drugs.